6-Hydroxydopamine (6-OHDA), 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) are important pharmacological tools used to produce selective chemical denervation of noradrenergic, dopaminergic and serotonergic neurons. The primary objective of this project will be to further elucidate the molecular mechanisms through which these agents produce their neurotoxicity. This objective will be accomplished by the synthesis and biological evaluation of specfic analogs of these neurotoxins. These chemical probes will be used to differentiate in vivo the relative importance of the two proposed molecular mechanisms of cytotoxicity. In addition, 6-OHDA, 5,6-DHT and 5,7-DHT will be dually labeled with (3H) at positions thought to be reactive in vivo with protein nucleophiles and with a chemically and metabolically stable (14C)-label as a reference marker. These (3H), (14C)-labeled chemical probes will be used to characterize the structures of the adducts formed in vivo when those neurotoxins react with endogenous protein neucleophiles. The results of these studies should improve our understanding of the molecular mechanism by which these agents produce neurotoxicity and permit the design of more specific-target-directed neurocytotoxins. Such specific neurocytotoxic agents would be valuable tools for studying the intricacies of the central nervous system.